Current treatment options for alcohol use disorders result in low compliance and high relapse rates for most patients. In order to develop novel therapeutic options, enhanced understanding of alternative pathways that mediate alcohol abuse is needed. The goal of this project is to better understand the mechanism and locus of action by which neurosteroid production affects alcohol intake, and how extrasynaptic GABAA receptors influence ethanol reinforcement. Aim 1 of this study will measure the extent to which NAc neurosteroid levels and extrasynaptic GABAA receptor activation alter ethanol self-administration. The influence of neurosteroid levels in the nucleus accumbens on alcohol drinking will be tested using mice trained in an operant self-administration paradigm. In addition, the effects of an extrasynaptic GABAA receptor agonist will examine the role of this subclass of receptors in the NAc on alcohol drinking. Aim 2 will measure the extent to which systemic neurosteroid levels and extrasynaptic GABAA receptor activation affect ethanol reinstatement. The dose response curve of a synthetic neurosteroid on reinstatement behavior will be measured to examine the influence of neurosteroid levels on alcohol seeking. Further, the involvement of extrasynaptic GABAA receptors will be tested to reveal whether this subclass of receptors is involved in alcohol reinstatement. Stimuli previously paired with alcohol, as well as exposure to alcohol, can be a potent trigger of alcohol-seeking and relapse in detoxifying users. Therefore, the effect of the neurosteroid agonist or extrasynaptic GABAA receptor agonist on oral ethanol or cue-induced reinstatement will also be examined to provide novel insight into mechanisms underlying relapse. This proposal will test the hypothesis that neurosteroid levels and extrasynaptic GABAA receptor activation are important determinants of ethanol intake and seeking, and that this effect is in part mediated by the NAc. PUBLIC HEALTH RELEVANCE: Alcohol use disorders can be a dangerous and expensive burden on society. The long-term goal of this project is to enhance understanding of neurosteroid pathways and receptor localizations that mediate alcohol abuse, in order to shed light on novel therapeutic options.